Outline

Best's vitelliforme macular dystrophy represents a rare autosomal dominant hereditary form of macular dystrophy. The main characteristics are an early onset of the disease and a reduction in the light-peak to dark ratio in the patient's EOG. Since the vitelliforme macular dystrophy share many similarities with age-related macular degeneration the understanding of the patho-mechanisms of Best's disease would improve the understanding of mechanisms leading to age-related macular degeneration. The cause for Best's macular dystrophy are mutations in the gene for bestrophin. 4 different homologues of bestrophin are known from which bestrophin 2-4 were found to be expressed in the CNS, colon and skeletal muscle. The function of the bestrophins is not fully understood.

Bestrophin-1 is a membrane protein exclusively expressed in the retinal pigment epithelium (RPE) where it is localised in the basolateral membrane. It physically interacts with the phosphatase PPA2. During the last 2 years betrophins 1 and 2 were described as members of a family of Ca2+-dependent Cl channels. This would explain the reduction in the light-peak because the light-peak is generated by activation of basolateral Cl conductance in the RPE. The reduction of the light-peak in the patients EOG would be explained by a loss of Cl channel function in all so far investigated mutant forms. However, there are other observations which challenge this hypothesis. First, with the knowledge of the bestrophin-1 gene, new mutations could be described from patients with macular dystrophy showing normal light-peaks. Furthermore, the Cl channel function of bestrophin in heterologeous expression systems could not be reproduced by all groups. In addition, bestrophin-1 was found to alter activity of voltage-gated Ca2+ channels by means of their time- and voltage-dependency. 2 investigated mutant bestrophins showed different effects on the time-dependent activation and inactivation of Ca2+-channels. Investigation of the light-peak in the rat EOG revealed a contribution of Ca2+-channels in the generation of the light-peak. Changes in the light-peak amplitude after transfection with wild-type or mutant bestrophin-1 were in accordance with observed changes in Ca2+-channel activity.

In summary, there are two alternative models of the bestrophin-1 function. Investigation of transgenic or bestrophin deficient mice would either combine these two models or lead to rejection of one of the two models. Due to the different expression patterns the study of the bestrophin function would improve the understanding of function other tissues.